One-pot three-component reaction between 2-aminopyridines, aldehydes and Meldrum's acid in water: An efficient synthesis of β-amino acids

Article abstract of DOI:10.1055/s-0028-1087279

A novel, one-pot, three-component synthesis of β-amino acids is described. Heating an alkaline aqueous solution of a 2-aminopyridine, an aldehyde and Meldrum's acid afforded β-amino acids in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087279

LETTER
3177
One-Pot Three-Component Reaction between 2-Aminopyridines, Aldehydes
and Meldrum’s Acid in Water: An Efficient Synthesis of b-Amino Acids
A
a
n
E
fficient Synthesis
e
of
b
-
Amino
h
A
cids di Adib,*a Solmaz Fatemi,a Meisam Nosrati,a Hamid Reza Bijanzadehb
b
Received 30 June 2008
eral diversity elements in a single chemical event. Typi-
cally, purification of products resulting from MCRs is
also simple since all the organic reagents employed are
consumed and are incorporated into the target compound.
MCRs, leading to interesting biologically active organic
compounds, are particularly useful for the construction of
diverse chemical libraries of ‘drug-like’ molecules.3
Abstract: A novel, one-pot, three-component synthesis of b-amino
acids is described. Heating an alkaline aqueous solution of a 2-ami-
nopyridine, an aldehyde and Meldrum’s acid afforded b-amino ac-
ids in good to excellent yields.
Key words: b-amino acids, 2-aminopyridines, aldehydes, Meldrum’s
acid, three-component reactions, synthesis in water
Development of new routes for b-amino acids synthesis
has become an important and challenging endeavor for or-
ganic chemists due to their biologically important proper-
ties, their occurrence in natural products, and as potential
precursors for b-lactams.4 The b-amino acids in free form
show interesting pharmacological properties. For in-
stance, hypoglycemic and antiketogenic activities were
observed in rats after oral intake of emeriamine (1;
Figure 1).5 Cispentacin (2; Figure 1) is an antifungal anti-
biotic.4 Functionalized b-amino acids are key components
of a variety of bioactive molecules such as taxol (3;
Figure 1), one of the most active antitumor agents which
contains phenylisoserine as its side chain.4 Furthermore,
b-amino acids, although not as abundant as their a-ana-
logues, are also segments in peptidic natural products with
various biological activities. b-Tyrosine, a b-aryl-b-amino
acid, is present in jasplakinolide (4; Figure 1) which is a
sponge metabolite with potent insecticidal, antifungal,
and antihelminthic properties.6
Water is a desirable solvent for chemical reactions be-
cause it is safe, nontoxic, environmentally friendly, readi-
ly available and cheap compared to organic solvents.1
Although enzymatic processes in nature occur in aqueous
environment by necessity, water has been avoided as a
solvent for common organic reactions due to poor solubil-
ity and, in some cases, the instability of organic reagents
or reaction intermediates in aqueous solutions. Since the
pioneering studies on Diels–Alder reactions by Breslow,2
there has been increasing recognition that organic reac-
tions can proceed well in aqueous media and offer advan-
tages over those occurring in organic solvents, such as rate
enhancement and insolubility of the final products that fa-
cilitates their isolation.1
Multicomponent reactions (MCRs) have emerged as an
efficient and powerful tool in modern synthetic organic
chemistry due to their valued features such as atom econ-
omy, straightforward reaction design and the opportunity
to construct target compounds by the introduction of sev-
NH2
OH
+
–
Me3N
CO2
CO2H
NH2
O
emeriamine (1)
cispentacin (2)
Br
O
HN
HN
O
O
AcO
O
OH
N
BzNH
O
O
NH
OH
O
HO
taxol (3)
AcO
O
OBz
jasplakinolide (4)
Figure 1
SYNLETT 2008, No. 20, pp 3177–3179
1
6
.1
2
.2
0
0
8
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087279; Art ID: D24308ST
© Georg Thieme Verlag Stuttgart · New York

3178
M. Adib et al.
LETTER
Table 1 Synthesis of b-Amino Acids 8a–qa
So far the most common synthetic routes reported for the
synthesis of b-amino acids involve: i) homologation of a-
amino acids, ia) Arndt–Eistert homologation, ib) synthe-
sis of b-amino acids starting from aspartic acid, aspar-
agine and its derivatives; ii) additions to double bonds, iia)
addition of enolates, silyl enolates or Reformatsky re-
agents to imines and iib) addition of carbon nucleophiles
to nitrones or oximes; iii) Curtius rearrangement of func-
tionalized succinates; iv) conjugate addition of nitrogen
nucleophiles to a,b-unsaturated acid derivatives (a,b-US-
ADs) and carbon nucleophiles to b-amino-a,b-USADs; v)
reductions, va) catalytic hydrogenation of b-amino-a,b-
USADs and vb) reductive amination of a,b-USADs; and
vi) amino hydroxylation of a,b-USADs.4,7
8
a
b
c
R1
R2
Yield (%)b
95
H
Ph
H
4-ClC6H4
4-FC6H4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
Ph
95
H
90
d
e
H
92
H
87
f
H
95
g
h
i
4-Me
4-Me
4-Me
5-Me
5-Me
5-Me
5-Me
H
98
4-FC6H4
4-MeC6H4
Ph
94
As part of our continuing effort on the design of new
routes for the preparation of biologically active organic
compounds,8 herein, we describe a novel, one-pot, three-
component synthesis of b-amino acids. Thus, a 2-amino-
pyridine 5, an aldehyde 6 and Meldrum’s acid (7) were
condensed at 100 °C in alkaline aqueous solution to pro-
duce the corresponding b-amino acids 8 in 74–98% yields
(Scheme 1, Table 1). All the reactions went to completion
within 1.5 hours.9 1H NMR analysis of the reaction mix-
tures clearly indicated formation of the corresponding
b-amino acids 8a–q in good to excellent yields.
93
j
95
k
l
4-FC6H4
4-MeC6H4
4-MeOC6H4
Pr
87
90
m
n
o
p
q
88
80
H
i-Pr
75
R1
4-Me
4-Me
Pr
82
R1
H2O
R2
O
O
O
KOH
R2CHO +
i-Pr
74
+
100 °C
1.5 h
O
O
N
N
H
OH
a Compounds 8a–m were crystallized from the reaction mixture.
N
NH2
Compounds 8n–q were purified by column chromatography (eluent:
5
6
7
8
EtOAc).
b Isolated yields.
Scheme 1
ppm), a methylene (d = 41.91 ppm), a methine (d = 51.01
ppm) and a carbonyl group (d = 172.10 ppm) as well as
nine distinct resonances in agreement with the proposed
structure.9
The structures of the b-amino acids 8a–q were deduced
1
on the basis IR, H and 13C NMR spectroscopy, mass
spectrometry and elemental analysis. The mass spectrum
of 8d displayed the molecular ion [M+] peak at m/z = 256
which was consistent with the product structure. The IR
spectrum of 8d showed absorptions at 3260, 2500–3350
(br) and 1713 cm–1 indicating the presence of NH, acid
A mechanistic rationalization for this reaction is provided
in Scheme 2. The first step may involve condensation of
the aldehyde with the 2-aminopyridine and formation of
aldimine 9, which may be attacked by enol tautomer of
Meldrum’s acid 10 leading to adduct 11. This adduct may
undergo nucleophilic addition of water followed by re-
moval of an acetone and a carbon dioxide molecule to af-
ford b-aryl-b-amino acids 8. These events facilitate in
alkaline solution.
1
OH and acid C=O functionalities, respectively. The H
NMR spectrum of 8d exhibited a sharp singlet (d = 2.23
ppm) as arising from the methyl group. An ABX system
(CHAHBCHX) was observed for the two diastereotopic H
2
atoms of the methylene group (dA = 2.63 ppm, dd, J =
3
2
15.3 Hz, J = 6.3 Hz; dB = 2.78 ppm, dd, J = 15.3 Hz,
3J = 8.4 Hz) and the adjacent methine H atom (dX = 5.29
ppm, multiplet). The characteristic signals for the eight H
atoms of the 2-pyridyl and aryl substituents were seen
with appropriate chemical shifts and coupling constants.
A fairly sharp doublet (d = 7.01 ppm, J = 8.5 Hz) was ob-
served for the NH group because of coupling with the ad-
jacent methine H atom. A broad signal (d = 12.00 ppm)
In conclusion, herein, we have reported that the one-pot
three-component reaction between 2-aminopyridines, al-
dehydes and Meldrum’s acid in water provide a conve-
nient, simple, efficient, and environmentally friendly
approach for the synthesis of b-amino acids of potential
synthetic and pharmacological interest. Use of water as a
green medium, use of simple starting materials, good to
excellent yields of the products and a simple purification
process (for aromatic aldehydes) are the main advantages
of this method. The simplicity of this method makes it an
interesting alternative to other approaches.
1
was observed for the carboxylic acid OH group. The H
decoupled 13C NMR spectrum of 8d showed four signals
readily recognized as arising from a methyl (d = 20.54
Synlett 2008, No. 20, 3177–3179 © Thieme Stuttgart · New York

LETTER
An Efficient Synthesis of b-Amino Acids
3179
H. R. Synlett 2006, 1765. (f) Adib, M.; Ghanbary, K.;
– OH
Mostofi, M.; Bijanzadeh, H. R. Tetrahedron 2005, 61, 2645.
(9) Procedure for the Preparation of 3-Phenyl-3-(2-
pyridylamino)propanoic Acid (8a): A mixture of 2-
aminopyridine (0.188 g, 2 mmol), benzaldehyde (0.212 g,
2 mmol), Meldrum’s acid (0.288 g, 2 mmol) and KOH
(0.056 g, 1 mmol) in H2O (5 mL) was stirred at 100 °C for
1.5 h, then the reaction mixture was cooled to r.t. and left
overnight. The product was obtained as colorless crystals.
Yield: 0.46 g (95%); mp 94–95 °C. IR (KBr): 3250 (NH),
2450–3300 (OH), 1710 (C=O), 1676, 1618, 1543, 1443,
1420, 1356, 1286, 1167, 1086, 962, 764, 700 cm–1. 1H NMR
(500.1 MHz, DMSO-d6): d = 2.69 (dd, 2J = 15.4 Hz, 3J = 6.3
Hz, 1 H, CH), 2.83 (dd, 2J = 15.4 Hz, 3J = 8.5 Hz, 1 H, CH),
5.35–5.41 (m, 1 H, CH), 6.46 (dd, J = 6.2, 6.3 Hz, 1 H, CH),
6.51 (d, J = 8.4 Hz, 1 H, CH), 7.08 (d, J = 8.5 Hz, 1 H, NH),
7.20 (t, J = 7.5 Hz, 1 H, CH), 7.30 (dd, J = 7.4, 7.6 Hz, 2 H,
2 × CH), 7.34 (dt, J = 1.7, 7.9 Hz, 1 H, CH), 7.42 (d, J = 7.9
Hz, 2 H, 2 × CH), 7.93 (dd, J = 1.4, 4.5 Hz, 1 H, CH), 12.10
(br, 1 H, OH). 13C NMR (125.8 MHz, DMSO-d6): d = 41.93
(CH2), 51.26 (CH), 108.41, 111.90, 126.60, 126.67, 128.14,
136.67 (6 × CH), 143.64 (C), 147.36 (CH), 157.86 (NCN),
172.12 (C=O). MS: m/z (%) = 242 (58) [M+], 224 (8), 197
(97), 183 (100), 122 (10), 104 (24), 94 (29), 78 (56), 67 (20),
51 (19). Anal. Calcd for C14H14N2O2 (242.28): C, 69.41; H,
5.82; N, 11.56. Found: C, 69.3; H, 5.9; N, 11.4.
H
O
O
R2
R2CHO
O
+
N
N
N
NH2
O
H
HO
5
6
9
10
R2
R2
O
O
OH2
O
O
O
N
N
H
N
N
OH
– acetone
– CO2
H
11
8
Scheme 2
Acknowledgment
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
References and Notes
(1) (a) Li, C.-J.; Chan, T. H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997. (b) Organic Synthesis in
Water; Grieco, P. A., Ed.; Thomson Science: Glasgow
Scotland, 1998. (c) Li, C.-J. Chem. Rev. 2005, 105, 3095.
(2) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159.
(b) Breslow, R. Acc. Chem. Res. 2004, 37, 471.
3-(4-Methylphenyl)-3-(2-pyridylamino)propanoic Acid
(8d): yield: 0.47 g (92%); colorless crystals; mp 99–100 °C.
IR (KBr): 3260 (NH), 2500–3350 (OH), 1713 (C=O), 1676,
1620, 1541, 1512, 1462, 1444, 1410, 1364, 1285, 1078, 962,
818, 760, 723 cm–1. 1H NMR (500.1 MHz, DMSO-d6): d =
2.23 (s, 3 H, Me), 2.63 (dd, 2J = 15.3 Hz, 3J = 6.3 Hz, 1 H,
CH), 2.78 (dd, 2J = 15.3 Hz, 3J = 8.4 Hz, 1 H, CH), 5.26–5.32
(m, 1 H, CH), 6.43 (dd, J = 5.9, 6.1 Hz, 1 H, CH), 6.47 (d,
J = 8.4 Hz, 1 H, CH), 7.01 (d, J = 8.5 Hz, 1 H, NH), 7.07 (d,
J = 7.9 Hz, 2 H, 2 × CH), 7.28 (d, J = 7.9 Hz, 2 H, 2 × CH),
7.31 (dt, J = 1.6, 7.8 Hz, 1 H, CH), 7.90 (d, J = 3.9 Hz, 1 H,
CH), 12.00 (br, 1 H, OH). 13C NMR (125.8 MHz, DMSO-
d6): d = 20.54 (Me), 41.91 (CH2), 51.01 (CH), 108.34,
111.82, 126.49, 128.66 (4 × CH), 135.66 (C), 136.61 (CH),
140.53 (C), 147.30 (CH), 157.85 (NCN), 172.10 (C=O).
MS: m/z (%) = 256 (69) [M+], 238 (17), 211 (94), 197 (100),
178 (9), 117 (25), 105 (20), 98 (13), 91 (28), 78 (56), 65 (11),
51 (13). Anal. Calcd for C15H16N2O2 (256.30): C, 70.29; H,
6.29; N, 10.93. Found: C, 70.3; H, 6.4; N, 10.8.
3-(2-Pyridylamino)hexanoic Acid (8n): yield: 0.33 g
(80%); colorless crystals; mp 52–54 °C. IR (KBr): 3264
(NH), 2500–3400 (OH), 1707 (C=O), 1676, 1615, 1540,
1443, 1417, 1350, 1282, 1170, 1080, 980 cm–1. 1H NMR
(300.1 MHz, DMSO-d6): d = 0.84 (t, J = 7.2 Hz, 3 H, Me),
1.22–1.40 (m, 2 H, CH2), 1.42–1.54 (m, 2 H, CH2), 2.31 (dd,
2J = 14.9 Hz, 3J = 6.9 Hz, 1 H, CH), 2.48 (dd, 2J = 14.9 Hz,
3J = 6.2 Hz, 1 H, CH), 4.18–4.23 (m, 1 H, CH), 6.32 (d, J =
8.0 Hz, 1 H, NH), 6.42 (dd, J = 6.0, 6.2 Hz, 1 H, CH), 6.44
(d, J = 8.0 Hz, 1 H, CH), 7.31 (dt, J = 1.6, 7.9 Hz, 1 H, CH),
7.92 (d, J = 4.3 Hz, 1 H, CH), 11.75 (br, 1 H, OH). 13C NMR
(75.5 MHz, DMSO-d6): d = 14.38 (Me), 19.22, 36.84, 40.15
(3 × CH2), 47.36 (CH), 108.83, 111.71, 136.98, 147.81 (4 ×
CH), 158.84 (NCN), 173.60 (C=O). MS: m/z (%) = 209
(100) [M+ + 1], 208 (81) [M+], 192 (18), 179 (9), 165 (36),
149 (72), 135 (16), 121 (84), 107 (19), 94 (55), 78 (57), 67
(25). Anal. Calcd for C11H16N2O2 (208.26): C, 63.44; H,
7.74; N, 13.45. Found: C, 63.2; H, 7.8; N, 13.2.
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